Mass spectrometric assays monitoring the deubiquitinase activity of the SARS-CoV-2 papain-like protease inform on the basis of substrate selectivity and have utility for substrate identification.
The SARS-CoV-2 papain-like protease (PLpro) and main protease (Mpro) are nucleophilic cysteine enzymes that catalyze hydrolysis of the viral polyproteins pp1a/1ab. By contrast with Mpro, PLpro is also a deubiquitinase (DUB) that accepts post-translationally modified human proteins as substrates. Here we report studies on the DUB activity of PLpro using synthetic Nε-lysine-branched oligopeptides as substrates that mimic post-translational protein modifications by ubiquitin (Ub) or Ub-like modifiers (UBLs), such as interferon stimulated gene 15 (ISG15). Mass spectrometry (MS)-based assays confirm the DUB activity of isolated recombinant PLpro. They reveal that the sequence of both the peptide fragment derived from the post-translationally modified protein and that derived from the UBL affects PLpro catalysis; the nature of substrate binding in the S sites appears to be more important for catalytic efficiency than binding in the S' sites. Importantly, the results reflect the reported cellular substrate selectivity of PLpro, i.e. human proteins conjugated to ISG15 are better substrates than those conjugated to Ub or other UBLs. The combined experimental and modelling results imply that PLpro catalysis is affected not only by the identity of the substrate residues binding in the S and S' sites, but also by the substrate fold and the conformational dynamics of the blocking loop 2 of the PLpro:substrate complex. Nε-Lysine-branched oligopeptides thus have potential to help the identification of PLpro substrates. More generally, the results imply that MS-based assays with Nε-lysine-branched oligopeptides have potential to monitor catalysis by human DUBs and hence to inform on their substrate preferences.


Hypothalamic Integration of Metabolic, Endocrine, and Circadian Signals in Fish: Involvement in the Control of Food Intake.
The regulation of food intake in fish is a complex process carried out through several different mechanisms in the central nervous system (CNS) with hypothalamus being the main regulatory center. As in mammals, a complex hypothalamic circuit including two populations of neurons: one co-expressing neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and the second one population co-expressing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) is involved in the integration of information relating to food intake control. The production and release of these peptides control food intake, and the production results from the integration of information of different nature such as levels of nutrients and hormones as well as circadian signals. The present review summarizes the knowledge and recent findings about the presence and functioning of these mechanisms in fish and their differences vs. the known mammalian model.


Dual catalytic apparatus of the thiamin diphosphate coenzyme: acid-base via the 1',4'-iminopyrimidine tautomer along with its electrophilic role.
It was recently reported (Jordan, F.; Zhang, Z.; Sergienko, E. A. Bioorg. Chem. 2002, 30, 188-198) that addition to the E477Q active-center variant of yeast pyruvate decarboxylase of (a) pyruvate on a rapid-scan UV stopped-flow, or (b) acetaldehyde or benzoylformate on a circular dichroism (CD) instrument, generates a new band with lambda(max) near 300-310 nm. A chemical model demonstrated that the wavelength is appropriate to the 1',4'-iminopyrimidine tautomer of the 4'-aminopyrimidine ring in thiamin diphosphate. Herein, we report the formation of a new positive CD band centered at 305 nm when the Escherichia colipyruvate dehydrogenase complex first E1 subunit and its variants are exposed to phosphonolactylthiamin diphosphate, a stable analogue of the covalent adduct formed between the substrate pyruvate and the C2 atom of thiamin diphosphate. The behavior of this CD band, whether it suggests saturation of the enzyme by phosphonolactylthiamin diphosphate, or its very existence (the band is not seen with the E571A E1 variant, where E571 is hydrogen bonded to the N1' atom of the 4'-aminopyrimidine ring), as well as its position are consistent with its assignment to the 1',4'-imino thiamin diphosphate tautomer on the enzyme, chiral by virtue of its fixed V conformation. The mechanism of binding of phosphonolactylthiamin diphosphate closely resembles that of thiamin diphosphate itself.


Lessons from the National Outcomes Measurement System (NOMS).
Significant reforms in education are changing the way school-based speech-language pathologists document and provide treatment. Faced with resource constraints and new mandates for accountability, clinicians are being pressured to demonstrate the value and impact of their services. To assist clinicians with meeting these challenges, the American Speech-Language-Hearing Association developed the National Outcomes Measurement System (NOMS) as a way to determine the effectiveness of school-based speech and language services. Data collected from NOMS are used to discuss: the effects of speech and language intervention on a student's ability to perform in the classroom, the key factors influencing progress for preschoolers with articulation disorders, and the impact of a clinician's caseload size on the outcomes students achieve.


Airflow obstruction after substance P aerosol: contribution of airway and pulmonary edema.
We have studied the effects of aerosolized substance P (SP) in guinea pigs with reference to lung resistance and dynamic compliance changes and their recovery after hyperinflation. In addition, we have examined the concomitant formation of airway microvascular leakage and lung edema. Increasing breaths of SP (1.5 mg/ml, 1.1 mM), methacholine (0.15 mg/ml, 0.76 mM), or 0.9% saline were administered to tracheostomized and mechanically ventilated guinea pigs. Lung resistance (RL) increased dose dependently with a maximum effect of 963 +/- 85% of baseline values (mean +/- SE) after SP (60 breaths) and 1,388 +/- 357% after methacholine (60 breaths). After repeated hyperinflations, methacholine-treated animals returned to baseline, but after SP, mean RL was still raised (292 +/- 37%; P less than 0.005). Airway microvascular leakage, measured by extravasation of Evans Blue dye, occurred in the brain bronchi and intrapulmonary airways after SP but not after methacholine. There was a significant correlation between RL after hyperinflation and Evans Blue dye extravasation in intrapulmonary airways (distal: r = 0.89, P less than 0.005; proximal: r = 0.85, P less than 0.01). Examination of frozen sections for peribronchial and perivascular cuffs of edema and for alveolar flooding showed significant degrees of pulmonary edema for animals treated with SP compared with those treated with methacholine or saline. We conclude that the inability of hyperinflation to fully reverse changes in RL after SP may be due to the formation of both airway and pulmonary edema, which may also contribute to the deterioration in RL.


Observational Review and Analysis of Concussion: a Method for Conducting a Standardized Video Analysis of Concussion in Rugby League.
Several professional contact and collision sports have recently introduced the use of sideline video review for club medical staff to help identify and manage concussions. As such, reviewing video footage on the sideline has become increasingly relied upon to assist with improving the identification of possible injury. However, as yet, a standardized method for reviewing such video footage in rugby league has not been published. The aim of this study is to evaluate whether independent raters reliably agreed on the injury characterization when using a standardized observational instrument to record video footage of National Rugby League (NRL) concussions. Video footage of 25 concussions were randomly selected from a pool of 80 medically diagnosed concussions from the 2013-2014 NRL seasons. Four raters (two naïve and two expert) independently viewed video footage of 25 NRL concussions and completed the Observational Review and Analysis of Concussion form for the purpose of this inter-rater reliability study. The inter-rater reliability was calculated using Cohen's kappa (κ) and intra-class correlation (ICC) statistics. The two naïve raters and the two expert raters were compared with one another separately. A considerable number of components for the naïve and expert raters had almost perfect agreement (κ or ICC value ≥ 0.9), 9 of 22 (41%) components for naïve raters and 21 of 22 (95%) components for expert raters. For the concussion signs, however, the majority of the rating agreement was moderate (κ value 0.6-0.79); both the naïve and expert raters had 4 of 6 (67%) concussion signs with moderate agreement. The most difficult concussion sign to achieve agreement on was blank or vacant stare, which had weak (κ value 0.4-0.59) agreement for both naïve and expert raters. There appears to be value in expert raters, but less value for naive raters, in using the new Observational Review and Analysis of Concussion (ORAC) Form. The ORAC Form has high inter-rater agreement for most data elements, and it can be used by expert raters evaluating video footage of possible concussion in the NRL.


Impact of a homeopathic medication on upper respiratory tract infections in COPD patients: Results of an observational, prospective study (EPOXILO).
Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder in which airflow is obstructed. Viral or bacterial upper respiratory tract infections (URTIs) may lead to exacerbations. Homeopathic medication administration to COPD patients during the influenza-exposure period may help to reduce the frequency of common URTIs. This prospective, observational, multicenter study was carried out in Cantabria, Spain. Patients with COPD were divided into two groups: group 1 received conventional treatment + homeopathic medication (diluted and dynamized extract of duck liver and heart; Boiron) (OG); group 2 received conventional treatment only (CG). The primary endpoint was the number of URTIs between the 4-5 months follow up (mean 4.72 ± 0.96) from basal to last visit. Secondary endpoints included the duration of URTIs, number and duration of COPD exacerbations, use of COPD drugs, changes in quality of life (QoL), compliance, and adverse events (AEs). 219 patients were analyzed (OG = 109, CG = 110). There was a significant reduction in mean number of URTIs during the follow-up period in OG compared to CG (0.514 ± 0.722 vs. 1.037 ± 1.519, respectively; p = 0.014). Logistic regression analysis showed a 3.3-times higher probability of suffering ≥2 URTI episodes in CG (p = 0.003, n = 72). OG patients having ≥1 URTI also had a significant reduction in mean URTI duration per episode (3.57 ± 2.44 days OG vs. 5.22 ± 4.17 days CG; p = 0.012). There was no significant difference in mean number of exacerbations, mean duration of exacerbations, or QoL between OG and CG. There was a greater decrease in proportion of patients using corticosteroids for exacerbations between baseline and visit 2 in OG compared to CG (22.1% vs. 7.5% fewer respectively, p = 0.005). Exacerbator phenotype patients had a significant decrease in number of URTIs (0.54 ± 0.72 vs. 1.31 ± 1.81; p = 0.011), and fewer COPD exacerbations (0.9 ± 1.3 vs. 1.5 ± 1.7; p = 0.037) in OG vs. CG, respectively. Homeopathic medication use during the influenza-exposure period may have a beneficial impact at reducing URTIs' number and duration in COPD patients and at reducing the number of COPD exacerbations in patients with the exacerbator phenotype. Further studies are needed to confirm the effects observed in this study.


Occupational performance: comparing normally-hearing and hearing-impaired employees using the Amsterdam Checklist for Hearing and Work.
This study compares the occupational performance of employees with and without hearing impairment, and aims to identify occupational difficulties specifically related to hearing loss. The Amsterdam Checklist for Hearing and Work was administered to 150 hearing-impaired employees and 60 normally-hearing colleagues. A multivariate analysis of variance was performed to test group effects, and to examine differences between means. Factors predicting sick-leave were identified by regression analyses. A significant group effect (p < 0.01) was found. Hearing-impaired employees differed from normally-hearing colleagues in their perception of 'environmental noise', 'job control' and the 'necessity to use hearing activities' at work. Also, sick-leave due to distress occurred significantly more often in the hearing impaired group (p < 0.05). 'Hearing impairment', 'job demand', and the requirement to 'recognize/distinguish between sounds' were the strongest risk-factors for stress related sick-leave. The importance of hearing functions besides speech communication is discussed. Implications for rehabilitation are suggested. In future research, hearing loss should be considered as a risk factor for fatigue and mental distress which may lead to sick-leave.


The impact of aging on epithelial barriers.
The epithelium has many critical roles in homeostasis, including an essential responsibility in establishing tissue barriers. In addition to the fundamental role in separating internal from external environment, epithelial barriers maintain nutrient, fluid, electrolyte and metabolic waste balance in multiple organs. While, by definition, barrier function is conserved, the structure of the epithelium varies across organs. For example, the skin barrier is a squamous layer of cells with distinct structural features, while the lung barrier is composed of a very thin single cell to minimize diffusion space. With the increased focus on age-dependent alterations in organ structure and function, there is an emerging interest in the impact of age on epithelial barriers. This review will focus on the impact of aging on the epithelial barrier of several organs, including the skin, lung, gastrointestinal tract and the kidney, at a structural and functional level.


Pediatric rehabilitation: 2. Environmental factors affecting participation.
This self-directed learning module highlights the environmental factors that influence the participation of children and youth with disabilities in life situations, including activities of self-care, mobility, socialization, education, recreation, and community life. It is part of the study guide on pediatric rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation and pediatric medicine. This module emphasizes the participation of children with disabilities in adapted sports and reviews mobility devices to promote function, in the context of the International Classification of Functioning and in reference to the Americans with Disabilities Act. It provides the physiatrist with strategies to promote community participation, functional independence and healthcare transitions for children with disabilities as they approach adulthood. The goal of this article is to improve the learner's treatment strategies to maximize the participation of children and youth with disabilities in all settings, particularly schools and communities.


Unauthorized medication collections on inpatient units.
Unauthorized medication collections (UMCs) on inpatient (IP) units represent a potential source of medication errors. UMCs are collections of medications not approved for storage and immediate access on IP units. We sought to establish whether UMCs were present on IP units in a suburban acute care hospital and to document the characteristics of any UMCs found. In this descriptive study, we searched all of the IP units in the hospital for unauthorized medications. We checked all medications found against current ward-stock lists to determine whether they were authorized, and we classified unauthorized medications into the following categories: high-alert, easily confused, expired and improperly stored medications, and controlled substances. All unauthorized medications found in various locations on a unit were considered one collection. We counted the number of unique products and total number of medications and calculated the total dollar value of the medications in each UMC. A UMC was found on each of the 17 IP units in the study hospital, resulting in a total of 656 unauthorized medications constituting 163 unique products. We documented high-alert, easily confused and expired medications and controlled substances. No unauthorized medications were improperly stored. Investigations are needed to determine why these UMCs exist and to formulate mechanisms to eliminate them. Knowing that UMCs may be present, nurses should search their workspace and remove any UMCs they find. They should also examine their nursing practice to determine if they are contributing to this unsafe practice.


Renpenning syndrome maps to Xp11.
Mutations in genes on the X chromosome are believed to be responsible for the excess of males among individuals with mental retardation. Such genes are numerous, certainly >100, and cause both syndromal and nonsyndromal types of mental retardation. Clinical and molecular studies have been conducted on the Mennonite family with X-linked mental retardation (XLMR) reported, in 1962, by Renpenning et al. The clinical phenotype includes severe mental retardation, microcephaly, up-slanting palpebral fissures, small testes, and stature shorter than that of nonaffected males. Major malformations, neuromuscular abnormalities, and behavioral disturbances were not seen. Longevity is not impaired. Carrier females do not show heterozygote manifestations. The syndrome maps to Xp11.2-p11.4, with a maximum LOD score of 3.21 (recombination fraction 0) for markers between DXS1039 and DXS1068. Renpenning syndrome (also known as "MRXS8"; gene RENS1, MIM 309500) shares phenotypic manifestations with several other XLMR syndromes, notably the Sutherland-Haan syndrome. In none of these entities has the responsible gene been isolated; hence, the possibility that two or more of them may be allelic cannot be excluded at present.


Of Fur, Feather, and Fin: Human's Use and Concern for Non-Human Species.
The public's concern for animal welfare is evolving and it is important to consider factors that are related to concern for animals and their use by humans. An online survey of 825 U.S. residents was conducted. Relationships between approval of animal uses and stated concern for animal welfare were examined. More than 90% of respondents reported that using animals for egg production, service or therapy, pets, and milk production was acceptable to them. Respondents who were younger or reported being female less frequently found most uses acceptable than older or male respondents. Half of respondents reported concern for the welfare of bison while 40% or more stated concern for the welfare of elk, beef cattle, and dairy cattle. Respondents who stated they were concerned for the welfare of dairy cattle less frequently reported accepting using animals for meat production, livestock shows, and hunting. Thus, self-reported concern for animal species and acceptance of the use of animals were related in some instances. A better understanding of the factors related to acceptance of animal uses and concern for animal welfare will help animal-related industries and wildlife agencies develop practices that are consistent with public attitudes.


Founding events in species invasions: genetic variation, adaptive evolution, and the role of multiple introductions.
Invasive species are predicted to suffer from reductions in genetic diversity during founding events, reducing adaptive potential. Integrating evidence from two literature reviews and two case studies, we address the following questions: How much genetic diversity is lost in invasions? Do multiple introductions ameliorate this loss? Is there evidence for loss of diversity in quantitative traits? Do invaders that have experienced strong bottlenecks show adaptive evolution? How do multiple introductions influence adaptation on a landscape scale? We reviewed studies of 80 species of animals, plants, and fungi that quantified nuclear molecular diversity within introduced and source populations. Overall, there were significant losses of both allelic richness and heterozygosity in introduced populations, and large gains in diversity were rare. Evidence for multiple introductions was associated with increased diversity, and allelic variation appeared to increase over long timescales (~100 years), suggesting a role for gene flow in augmenting diversity over the long-term. We then reviewed the literature on quantitative trait diversity and found that broad-sense variation rarely declines in introductions, but direct comparisons of additive variance were lacking. Our studies of Hypericum canariense invasions illustrate how populations with diminished diversity may still evolve rapidly. Given the prevalence of genetic bottlenecks in successful invading populations and the potential for adaptive evolution in quantitative traits, we suggest that the disadvantages associated with founding events may have been overstated. However, our work on the successful invader Verbascum thapsus illustrates how multiple introductions may take time to commingle, instead persisting as a 'mosaic of maladaptation' where traits are not distributed in a pattern consistent with adaptation. We conclude that management limiting gene flow among introduced populations may reduce adaptive potential but is unlikely to prevent expansion or the evolution of novel invasive behaviour.


Unique [3H]tryptamine binding sites in rat brain: distribution and pharmacology.
[3H]Tryptamine binding in rat brain is widely distributed with highest densities in the cortex, striatum and hippocampus. This binding is stereospecific and is potently displaced by tryptamine analogues and beta-carbolines. Phenethylamines also possess a weaker activity in displacing [3H]tryptamine. The strict structural requirements for binding to this site substantiate its unique character and suggest that it may represent a tryptamine receptor in the CNS.


Photoelectrochemical hydrogen evolution of tapered silicon nanowires.
The origin of the photocurrent enhancement and the overpotential reduction in solar water splitting employing nanostructured silicon is still a matter of debate. A set of tapered Si nanowires (SiNWs) has been designed for clarifying the impact of nanostructured Si on the hydrogen evolution reaction (HER) while precisely tailoring several interference factors such as surface area, light absorption and surface defect density. We find that defect passivation by KOH achieved by tapering is much more beneficial than the optical gain. Surfactant-mediated modification of SiNWs is capable of engineering the band structure. As a result, we suggest a guideline for nanostructured Si photoelectrodes optimized for the HER.


Experimental Design for Laser Microdissection RNA-Seq: Lessons from an Analysis of Maize Leaf Development.
Genes with important roles in development frequently have spatially and/or temporally restricted expression patterns. Often these gene transcripts are not detected or are not identified as differentially expressed (DE) in transcriptomic analyses of whole plant organs. Laser Microdissection RNA-Seq (LM RNA-Seq) is a powerful tool to identify genes that are DE in specific developmental domains. However, the choice of cellular domains to microdissect and compare, and the accuracy of the microdissections are crucial to the success of the experiments. Here, two examples illustrate design considerations for transcriptomics experiments; a LM RNA-seq analysis to identify genes that are DE along the maize leaf proximal-distal axis, and a second experiment to identify genes that are DE in liguleless1-R (lg1-R) mutants compared to wild-type. Key elements that contributed to the success of these experiments were detailed histological and in situ hybridization analyses of the region to be analyzed, selection of leaf primordia at equivalent developmental stages, the use of morphological landmarks to select regions for microdissection, and microdissection of precisely measured domains. This paper provides a detailed protocol for the analysis of developmental domains by LM RNA-Seq. The data presented here illustrate how the region selected for microdissection will affect the results obtained.


Treatment of advanced cervical cancer by combination of bleomycin and mitomycin-C.
A combination of bleomycin and mitomycin-C, reported as extraordinarily effective in a previous clinical trial, was used to treat 20 patients with advanced cervical cancer. Seven partial remissions (35%) and one complete remission (5%) were observed. Six of the partial remissions were of short duration (less than four months); the only patient with complete remission was still alive without evidence of disease ten months after initiation of chemotherapy. Nonresponders had a mean survival time of 6.6 months and responders 8.0 months. The treatment results confirm some efficacy of the drug regimen, although in our hands it did not live up to the high expectations raised by others.


Multienzyme system for dihydroxyacetone phosphate-dependent aldolase catalyzed C-C bond formation from dihydroxyacetone.
A multienzyme system composed by recombinant dihydroxyacetone kinase from Citrobacter freundii, fuculose-1-phosphate aldolase and acetate kinase, allows a practical one-pot C-C bond formation catalysed by dihydroxyacetone phosphate-dependent aldolases from dihydroxyacetone and an aldehyde.


Clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor.
The Epstein-Barr virus (EBV) encodes its own microRNAs (miRNAs); however, their biological roles remain elusive. The commonly used EBV B95-8 strain lacks a 12-kb genomic region, known as BamHI A rightward transcripts (BART) locus, where a number of BART miRNAs are encoded. Here, bacterial artificial chromosome (BAC) technology was used to generate an EBV B95-8 strain in which the 12-kb region was fully restored at its native locus [BART(+) virus]. Epithelial cells were stably infected with either the parental B95-8 virus or the BART(+) virus, and BART miRNA expression was successfully reconstituted in the BART(+) virus-infected cells. Microarray analyses of cellular gene expression identified N-myc downstream regulated gene 1 (NDRG1) as a putative target of BART miRNAs. The NDRG1 protein was barely expressed in B cells, highly expressed in epithelial cells, including primary epithelial cells, and strongly downregulated in the BART(+) virus-infected epithelial cells of various origins. Although in vitro reporter assays identified BART22 as being responsible for the NDRG1 downregulation, EBV genetic analyses revealed that BART22 was not solely responsible; rather, the entire BART miRNA cluster 2 was responsible for the downregulation. Immunohistochemical analyses revealed that the expression level of the NDRG1 protein was downregulated significantly in EBV-positive nasopharyngeal carcinoma specimens. Considering that NDRG1 encodes an epithelial differentiation marker and a suppressor of metastasis, these data implicate a causative relationship between BART miRNA expression and epithelial carcinogenesis in vivo. EBV-related epithelial cancers, such as nasopharyngeal carcinomas and EBV-positive gastric cancers, encompass more than 80% of EBV-related malignancies. Although it is known that they express high levels of virally encoded BART miRNAs, how these miRNAs contribute to EBV-mediated epithelial carcinogenesis remains unknown. Although a number of screenings have been performed to identify targets of viral miRNAs, many targets likely have not been identified, especially in case of epithelial cell infection. This is the first study to use EBV genetics to perform unbiased screens of cellular genes that are differentially expressed in viral miRNA-positive and -negative epithelial cells. The result indicates that multiple EBV-encoded miRNAs cooperatively downregulate NDRG1, an epithelial differentiation marker and suppressor of metastasis. The experimental system described in this study should be useful for further clarifying the mechanism of EBV-mediated epithelial carcinogenesis.


Association of the BDNF Val66Met polymorphism with BMI in chronic schizophrenic patients and healthy controls.
Several lines of evidence suggest that a functional variant of the brain-derived neurotrophic factor gene (BDNF Val66Met) correlates with a number of eating disorders. Studies have also shown that the BDNF Val66Met polymorphism was associated with weight gain in patients with schizophrenia on long-term antipsychotic treatment. This study aimed to determine whether there was a relationship between the BDNF Val66Met polymorphism and BMI values in patients with chronic schizophrenia. We compared 308 Han Chinese patients with schizophrenia on long-term antipsychotic medication with 304 healthy normal controls on BDNF polymorphism. Body weight and BMI were measured before breakfast on the day blood samples were taken. The symptomatology of schizophrenia was assessed using the Positive and Negative Syndrome Scale. The results showed that the BDNF Val66Met polymorphism was associated with the BMI value, with genotype having a strong effect on the mean BMI value in male but not in female patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment.


Combined use of serial serum human chorionic gonadotropin testing, ultrasound and panoramic diagnostic microhysteroscopy in the early diagnosis of ectopic pregnancy.
It is not always easy to make an early diagnosis of ectopic pregnancy in patients with suspected ectopic pregnancy who in any case appear to be clinically stable, and in whom the serial serum study of human chorionic gonadotropin (hCG) testing and ultrasound (US) showed an abnormal pregnancy without adding any useful information for obtaining a differential diagnosis between ectopic pregnancy and non-viable intrauterine pregnancy (IUP). Typical management of these patients comprises expectant observation or carrying out a diagnostic laparoscopy. The purpose of this study was to examine the value of microhysteroscopy as an adjunctive procedure in the above-mentioned patients; the results of this clinical test show that in these patients, the microhysteroscopy may represent a simple and valid alternative to expectant observation or immediate laparoscopy.


Enteroaggregative Escherichia coli heat-stable enterotoxin 1 (EAST1): a new toxin with an old twist.
Enteroaggregative Escherichia coli heat-stable enterotoxin 1 (EAST1) is a small protein that was first detected more than a decade ago in an enteroaggregative E. coli (EAEC) strain isolated from the stools of a diarrheic child. The EAST1 gene, astA, is not solely present in EAEC, but also in other categories of diarrheagenic E. coli. Strains expressing EAST1 have been shown to induce diarrhea principally in humans, although they have also been associated with piglets and calves. EAST1 toxin has been proposed as a virulence factor implicated in the mechanism of pathogenesis of EAEC and could play a role in the pathogenicity of other enteropathogens as well. This toxin is often compared to E. coli STa enterotoxin because they share some physical and mechanistic similarities. This review summarizes the various observations on EAST1 since its discovery.


Acetylcysteine: a drug that is much more than a mucokinetic.
Acetylcysteine is the most widely used mucolytic drug, and it has greater documentation of effectiveness than any other mucokinetic agent. Originally it was used as an aerosol, but currently it is mostly prescribed by the oral route. In addition to the lytic activities of acetylcysteine, the aerosolized drug has bronchorrheic effects, while oral therapy results in expectorant and mucoregulator actions. Newer uses of the drug depend on its effectiveness as a free-radical scavenger, since it is a precursor of glutathione. It is well established as the drug of choice for treating acetaminophen poisoning, and it offers an important role in protecting the lungs from a variety of insults that result in oxidant damage.


Studies of the toxicological potential of capsinoids: VI. Single-dose toxicity study and micronucleus test of commercial-grade dihydrocapsiate.
A single-dose oral toxicity study was conducted to examine the qualitative and quantitative toxicity of a commercial-grade batch of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2). Dihydrocapsiate was administered once by gavage to ICR mice at dose levels of 0 (vehicle) or 5000 mg/kg/day. No mortality was observed during the 14 day observation period following test article administration. During the 2 h immediately following dosing, mice of both sexes treated with dihydrocapsiate were observed to exhibit one or more of the following: staggered gait, decreased spontaneous movement, increased time in the prone position, tremors, gasping, or red-brownish urine. All mice had completely recovered by the 6 h observation interval. No effects on body weights or necropsy findings were observed as a result of dihydrocapsiate administration. These results suggested that the lethal dose of dihydrocapsiate was >5000 mg/kg. In an in vivo micronucleus test using BDF(1) male mice, a commercial grade of dihydrocapsiate neither increased the incidence of micronucleated polychromatic erythrocytes (MNPCEs) nor decreased the ratio of polychromatic erythrocytes (PCEs) in any of the treatment groups. The results suggest that commercial-grade dihydrocapsiate is unlikely to be an in vivo clastogen.


A strategy for dose-finding and safety monitoring based on efficacy and adverse outcomes in phase I/II clinical trials.
We propose a design strategy for single-arm clinical trials in which the goals are to find a dose of an experimental treatment satisfying both safety and efficacy requirements, treat a sufficiently large number of patients to estimate the rates of these events at the selected dose with a given reliability, and stop the trial early if it is likely that no dose is both safe and efficacious. Patient outcome is characterized by a trinary ordinal variable accounting for both efficacy and toxicity. Like Thall, Simon, and Estey (1995, Statistics in Medicine 14, 357-379), we use Bayesian criteria to generate decision rules while relying on frequentist criteria obtained via simulation to determine a design parameterization with good operating characteristics. The strategy is illustrated by application to a bone marrow transplantation trial for hematologic malignancies and a trial of a biologic agent for malignant melanoma.


[Effects of rapamycin on amyloid β-protein induced impairments of working memory and synaptic plasticity in rats].
The present study investigated the effects of rapamycin on Aβ1-42-induced deficits in working memory and synaptic plasticity. After bilateral hippocampal injection of Aβ1-42 and rapamycinin rats, spontaneous alternation in Y-maze and in vivo hippocampal long-term potentiation (LTP) of rats were recorded. All data were analized by two-way repeated measures analysis of variance (ANOVA). (Hippocampal injection of Aβ1-42 alone impaired working memory of rats; (2) Rapamycin did not affect working memory of rats, but alleviated Aβ1-42-induced working memory deficits, compared with Aβ1-42 alone group; (Aβ1-42 remarkably suppressed in vivo hippocampal LTP of fEPSPs in the CA1 region; (4) Pretreatment with rapamycin prevented Aβ1-42-induced suppression of LTP. These data indicates that rapamycin could protect against Aβ1-42-induced impairments in working memory and synaptic plasticity in rats.


Phenotypic and genetic analysis of HLA class I and HLA-DR antigen expression on human melanomas.
Class I and HLA-DR antigen expression were studied with histochemical techniques involving monomorphic monoclonal antibodies in 49 cases of human malignant melanomas, 20 primary and 29 metastatic. A large percentage (90%) of primary melanomas were positive for HLA class I, while those primary lesions showing lowest levels of class I antigen expression were at the upper end of the range of invasiveness and possessed a higher metastatic potential. Expression of HLA-DR molecules on primary melanomas was low (25% of all cases) and HLA-DR-positive melanomas were among the most aggressive. In metastatic melanomas, HLA class I expression was less common than in primary lesions. The lowest percentage of cases positive for HLA class I was found for cutaneous metastases. HLA-DR molecules were more frequently expressed by lymph node metastases than on primary melanomas. The comparison of the expression of HLA class I and HLA-DR molecules by primary melanomas and their autologous metastases revealed a high degree of heterogeneity. Class I genes were further studied by Southern blot assays. No differences were found in restriction fragments for class I genes among 4 melanomas and their autologous lymphocytes, 2 of which were positive and 2 negative for class I expression.


Improvement of hepatogenic differentiation of iPS cells on an aligned polyethersulfone compared to random nanofibers.
The application of stem cells holds great promises in cell and tissue transplants. This study was designed to compare the hepatogenic differentiation of iPSCs on aligned PES/COL versus random. Aligned and random PES/COL nanofibrus scaffolds were fabricated by electrospining and their surface modified through plasma treatment and collagen coating. The scaffolds were characterized using scanning electron microscopy (SEM) and ATR-FTIR. Morphology and biochemical activities of the differentiated hepatocyte-like cells (HLCs) were examined after 5 and 20 days of differentiation. Real-Time RT-PCR and ICC showed no significant difference in the mRNA and protein levels of two important definitive endoderm specific markers, including Sox17 and Foxa2 between two scaffolds. However, Real-Time RT-PCR analysis indicated an increase in the expression of Cyp7A1 gene over the period of the differentiation procedure on the aligned nanofibers but there was no difference in other genes such as Albumin and CK19. Moreover, comparison of hepatogenic differentiation evaluated by Albumin production in conditioned media of HLCs differentiated on aligned PES/COL, showed increase expression of these markers after 20 days compared to that of the random nanofibers. Taken together, the results of this study may indicate that aligned PES/COL nanofibrous scaffolds can improve terminal differentiation of HLCs from iPSCs.


Journal Club: Structured radiology reports are more complete and more effective than unstructured reports.
The radiology report serves as the primary method of communication about imaging findings. Traditional free-text (i.e., unstructured) radiology reporting entails dictating in a stream-of-consciousness manner. Structured reporting aims to standardize the format and lexicon used in reports. This standardization may improve the communication of findings, allowing ease of reading and comprehension. A structured reporting template may also be used as a checklist while reviewing a case, which may facilitate focused attention and analysis. The goal of this study was to compare unstructured and structured reports in terms of their completeness and effectiveness. Radiology trainees were given an educational lecture on the background of reporting and were provided with a structured reporting template for dictating chest radiographs. Twelve trainees completed the study. Sixty reports from before and 60 reports from after the intervention were each independently scored by four blinded physician raters for completeness and effectiveness. Structured reports were found to be statistically significantly more complete and more effective than unstructured reports (mean completeness score, 4.42 vs 3.99, p<0.001; mean effectiveness score, 4.11 vs 3.85, p<0.001). A combined score was calculated for each report and was higher for the structured reports (mean combined score, 8.54 vs 7.83, p<0.001). Structured chest radiograph reports were more complete and more effective than unstructured chest radiograph reports. Although additional studies are needed for validation, this study suggests that structured reporting may represent an improved reporting method for radiologists.


Clinical and ultrasonographic features of male breast tumors: A retrospective analysis.
The purpose of this study was to determine clinical and ultrasonographic characteristics of male breast tumors. The medical records of male patients with breast lesions were retrieved from an electronic medical record database and a pathology database and retrospectively reviewed. A total of 112 men (125 breast masses) with preoperative breast ultrasonography (US) were included (median age, 59.50 years; age range, 15-96 years). Data extracted included patient age, if the lesions were bilateral, palpable, and tender, and the presence of nipple discharge. Breast lesion features on static US images were reviewed by three experienced radiologists without knowledge of physical examination or pathology results, original breast US image interpretations, or surgical outcomes. The US features were documented according to the BI-RADS (Breast Imaging-Reporting and Data System) US lexicons. A forth radiologist compiled the data for analysis. Of the 125 breast masses, palpable tender lumps and bilateral synchronous masses were more likely to be benign than malignant (both, 100% vs 0%, P < 0.05). Advanced age and bloody discharge from nipples were common in malignant lesions (P <0.05). A mass eccentric to a nipple, irregular shape, the presence of an echogenic halo, predominantly internal vascularity, and rich color flow signal on color Doppler ultrasound were significantly related to malignancy (all, P < 0.05). An echogenic halo and the presence of rich color flow signal were independent predictors of malignancy. Specific clinical and US characteristics of male breast tumors may help guide treatment, and determine if surgery or conservative treatment is preferable.


Sexual and reproductive health trends among women with enduring mental illness: a survey of Western Australian community mental health services.
An exploratory cross-sectional survey was conducted to determine associations and potential modifiable risk factors for management of sexual and reproductive health needs for women attending community mental health services. Women (n = 220) had on average three pregnancies; 61.2% were unplanned. One quarter who were sexually active within the past 12 months denied using contraception with 51% using less effective methods. The majority (81.7%) engaged in Pap smear screening, and those with a general practitioner (GP) were more likely to participate (p =.004). Findings highlight GPs' potential in optimizing women's health. Considering unplanned pregnancies and contraception trends, we suggest improved access to contraception options, particularly long-acting reversible methods.


[Appendix mucinous cystadenoma].
Mucous cystadenomas are benign epithelial tumours with great mucous content inside. Despite being non-malignant, they acquired great size, compressing and displacing important structures and organs of the zone, with theirs unlucky outcomes. Surgical exeresis is very difficult, being almost impossible its total exeresis, showing great frequency of relapse. We present an appendix mucous cystadenoma case in a 54 years old patient.


Cycloalkanones. 7. Hypocholesterolemic activity of aliphatic compounds related to 2,8-dibenzylcyclooctanone.
A series of 19 aliphatic analogs of 2,8-dibenzylcyclooctanone and 1,5-diphenyl-2,4-dimethyl-3-pentanone was examined. Separation of hypocholesterolemic activity from the previously observed uterotropic and antifertility activities was achieved by simplification of the parent compound to 2-octanone. There was no loss of hypocholesterolemic activity. Reduction of serum cholesterol levels in male rats to less than 50% of control values was obtained at a dose of 10 mg/kg/day.


ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells.
Reactive oxygen species (ROS) have an important role in regulating various cellular processes. Our previous study confirmed that selenite, an anti-tumour agent, triggered apoptosis through the production of ROS in multiple types of cancer cells. In this study, we discovered that ROS also inhibited protective autophagy by decreasing the expression of ULK1, an initiator of autophagy, in selenite-treated NB4 cells. Further experiments demonstrated that p-p53 (S392), a phosphorylation event promoted by p70S6K, bound to the promoter of ULK1 and modulated its expression. Experiments in a mouse tumour model with NB4 cells provided in vivo confirmation of the alterations in the p70S6K/p53/ULK1 axis. Collectively, our results show that ROS inhibited autophagy by downregulating the p70S6K/p53/ULK1 axis in selenite-treated NB4 cells.


Genetic signatures of dominance hierarchies reveal conserved cis-regulatory and brain gene expression underlying aggression in a facultatively social bee.
Agonistic interactions among individuals can result in the formation of dominance hierarches that can reinforce individual behavior and social status. Such dominance hierarches precede the establishment of reproductive dominance, division of labor and caste formation in highly social insect taxa. As such, deciphering the molecular basis of aggression is fundamental in understanding the mechanisms of social evolution. Assessing the proximate mechanisms of aggression in incipiently social bees can provide insights into the foundations of genomic mechanisms of social behavior. Here, we measured the effects of aggression on brain gene expression in the incipiently social bee, Ceratina australensis. We examine the brain transcriptomic differences between individuals who have experienced recurrent winning, losing, or a change in rank during repeated encounters. Using comparative analyses across taxa, we identify deeply conserved candidate genes, pathways, and regulatory networks for the formation of social hierarchies.


Interactions between ethylene, gibberellin and abscisic acid regulate emergence and growth rate of adventitious roots in deepwater rice.
Growth of adventitious roots is induced in deepwater rice (Oryza sativa L.) when plants become submerged. Ethylene which accumulates in flooded plant parts is responsible for root growth induction. Gibberellin (GA) is ineffective on its own but acts in a synergistic manner together with ethylene to promote the number of penetrating roots and the growth rate of emerged roots. Studies with the GA biosynthesis inhibitor paclobutrazol revealed that root emergence was dependent on GA activity. Abscisic acid (ABA) acted as a competitive inhibitor of GA activity. Root growth rate on the other hand was dependent on GA concentration and ABA acted as a potent inhibitor possibly of GA but also of ethylene signaling. The results indicated that root emergence and elongation are distinct phases of adventitious root growth that are regulated through different networking between ethylene, GA and ABA signaling pathways. Adventitious root emergence must be coordinated with programmed death of epidermal cells which cover root primordia. Epidermal cell death is also controlled by ethylene, GA and ABA albeit with cell-type specific cross-talk. Different interactions between the same hormones may be a means to ensure proper timing of cell death and root emergence and to adjust the growth rate of emerged adventitious roots.


Development of protective inflammation and cell-mediated immunity against Cryptococcus neoformans after exposure to hyphal mutants.
Morphological switch is tightly coupled with the pathogenesis of many dimorphic fungal pathogens. Cryptococcus neoformans, the major causative agent of cryptococcal meningitis, mostly presents as the yeast form but is capable of switching to the hyphal form. The filamentous form has long been associated with attenuated virulence, yet the underlying mechanism remains elusive. We previously identified the master regulator Znf2 that controls the yeast-to-hypha transition in Cryptococcus. Activation of Znf2 promotes hyphal formation and abolishes fungal virulence in vivo. Here we demonstrated that the cryptococcal strain overexpressing ZNF2 elicited strong and yet temporally confined proinflammatory responses in the early stage of infection. In contrast, exacerbated inflammation in mice infected with the wild-type (WT) strain showed that they were unable to control the infection. Animals inoculated with this filamentous Cryptococcus strain had fewer pulmonary eosinophils and CD11c(+) CD11b(+) cells than animals inoculated with WT yeast. Moreover, mice infected with this strain developed protective Th1- or Th17-type T cell responses. These findings suggest that the virulence attenuation of the filamentous form is likely due to its elicitation of protective host responses. The antivirulence effect of Znf2 was independent of two previously identified factors downstream of Znf2. Interestingly, mucosal immunizations with high doses of ZNF2-overexpressing cells, either in the live or heat-killed form, offered 100% protection to the host from a subsequent challenge with the otherwise lethal clinical strain H99. Our results demonstrate that heat-resistant cellular components presented in cryptococcal cells with activated ZNF2 elicit protective host immune responses. These findings could facilitate future research on novel immunological therapies. Cryptococcal meningitis is one of the leading causes of death among AIDS patients. This disease presents a severe threat to public health. The current antifungal regimens are unsatisfactory in controlling or clearing the pathogen Cryptococcus neoformans. Immunotherapies and/or vaccines could be a promising approach to prevent or manage this deadly disease. However, the lack of understanding of host-pathogen interactions during cryptococcal infection greatly hampers the development of effective immunotherapies. In this study, we discovered that inoculation of cryptococcal cells with activated Znf2, a morphogenesis regulator and an antivirulence factor, could shift the host pathological Th2 responses to the protective Th1 or Th17 responses. Importantly, we discovered that vaccination with either the viable or heat-killed form of ZNF2-overexpressing cells protected animals from the otherwise lethal infection by the highly virulent clinical strain. Our study suggests that the fungal cellular component(s) of the ZNF2-overexpressing strain may provide potential vaccine candidate(s) for controlling the fatal disease.


A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat.
Autoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo. To explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat. PSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis. The frequency of 'TT' genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively). PSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype 'CC' advocates the vital role of PSMB8 in the autoimmune basis of vitiligo.


Family Context Moderates the Association of Maternal Postpartum Depression and Stability of Infant Temperament.
Maternal postpartum depression, maternal sensitivity, and family functioning were examined as predictors of the stability of observed infant temperament over the first 30 months of life (N = 147 families). Eight observations at 8, 15, and 30 months postpartum were used to assess infant temperament. Structured clinical interviews were used to assess maternal depression, and observational assessments were used to assess family functioning and maternal sensitivity. Family context moderated the effect of maternal depression on change in infant temperament. Maternal depression was associated with change in infant temperament when maternal sensitivity was low but not when maternal sensitivity was high. Family functioning similarly moderated these links. Results underscore the centrality of the family context in shaping child behavior over time.


Influence of soft tissue grafting, orofacial implant position, and angulation on facial hard and soft tissue thickness at immediately inserted and provisionalized implants in the anterior maxilla.
Resorption of hard and soft tissues following immediate implant insertion is frequently reported. Data regarding the influencing factors on facial tissue thickness are rare. This retrospective study investigated the impact of connective tissue grafting, the orofacial angulation and position of immediately inserted and provisionalized implants on the facial hard and soft tissue thickness in the anterior maxilla within a 1- to 5-year follow-up. Implants with the prerequisite of having preoperative and postoperative cone beam computed tomography (CBCT) and a follow-up of 1 to 5 years were included. Facial bone deficiencies were grafted flaplessly with autogenous bone in all sites. In a subgroup of implants additional connective tissue grafting was performed, whereas the remaining implants were not grafted with soft tissue. The orofacial tooth and implant angulation, the change of horizontal position and the facial bone thickness were measured by CBCT, the facial mucosa thickness by an ultrasonic device. In total, 76 implants were placed in 55 patients. Sixty-nine sites showed a facial bone defect. Thirty-eight received a connective tissue graft additionally. All implants were still in function after a mean follow-up of 36 months. The mean thickness of the facial mucosa was 1.72 mm at 1 mm, 1.63 mm at 4 mm, 1.52 mm at 6 mm, and 1.66 mm at 9 mm apically to mucosal margin. The bone thickness was 0.02, 0.25, and 0.36 mm initially and 1.32, 1.26, and 1.11 mm finally at 1, 3, and 6 mm apically to implant shoulder level. Mixed model analysis revealed an impact of the preoperative bone status on the facial bone increase. The facial soft tissue thickness was significantly influenced by the gingival biotype. The results indicate that an initial severe hard tissue defect allows for significant bone regeneration. The facial soft tissue thickness is primarily influenced by the gingival biotype.


Initial therapy for acute myeloid leukemia in older patients: principles of care.
Older patients with acute myeloid leukemia (AML) frequently have significant comorbidities, geriatric syndromes, and high-risk leukemia that make them susceptible to high early mortality, chemotherapy-related toxicities, and poor long-term survival. The receipt of chemotherapy or hematopoietic cell transplantation is low, and the choices between intensive or low-intensity chemotherapy is often not clear. Geriatric and multidisciplinary interventions targeted to optimize functional status and improve management of comorbidities may enhance chemotherapy tolerance. Comprehensive geriatric assessment, and other integrated risk assessment models have been developed to predict the risk of chemotherapy-related toxicities and survival, and may guide therapy assignment. Development of low intensity but effective therapy is a major need. Deeper understanding of the molecular biology of AML has allowed several novel therapies to enter clinical trials in recent years. Continuation of successful collaboration between several stakeholders will be necessary to build upon the clinical and research improvements made thus far.


Comparative clinical evaluation of the efficacy of a new method for caries diagnosis and excavation.
The purpose of this study is to compare the efficiency of fluorescence-aided caries excavation (FACE) to remove carious dentin primary teeth with that of conventional methods. After caries excavation was carried out, dentin surfaces were conventionally inspected using visual tactile criteria and 415 cavities which were classified as caries-free, re-inspected with Face-Light and caries detector dye (CDD) methods. Orange-red fluorescing areas classified as carious dentin, as well as stained carious dentin. All the data were recorded according to localization of the caries and determination efficiency of the methods. X(2) test was used to compare the mean values of both Face-Light and dye applications, while Wilcoxon test performed to evaluate the effectiveness for each diagnostic method. A total of 273 patients with 415 Class II (OM/OD) cavities (1.65 ± 0.52 teeth per patient) with carious lesions in molar and premolar teeth, were examined. Out of 415 teeth, in 149 teeth (35.9%) no caries findings had been illustrated. While FACE detected remaining carious or partially removed areas in 237 teeth (57.2%), CDD stained only 29 teeth by itself (P < 0.05). In conclusion, FACE has a higher detectability compared to visual inspection and caries detector dye in diagnosis and removal of carious dentin.


Content and distribution of glycogen in oral epithelial dysplasia.
Forty-four oral lesions with epithelial dysplasia and 25 other benign and malignant lesions of the oral mucosa were examined after staining with hematoxylin-eosin and diastase controlled PAS. The intensity of the PAS-positivity for glycogen, the grade of dysplasia, the type of keratinization and the degree of subepithelial inflammation were recorded. Histologically normal epithelium at the margins of the lesions were used as controls. The presence and amount of glycogen in normal epithelium at the margins of the lesions were used as controls. The presence and amount of glycogen in normal epithelium at the margin of the lesions were used as controls. The presence and amount of glycogen in normal epithelium varied with the form of keratinization in that non- or parakeratinized epithelium was rich in glycogen whereas there was a negative glycogen-reaction in orthokeratinized epithelium. The most striking feature was an abrupt limitation of the glycogen at the junction between nondysplastic and dysplastic epithelium. The difference in the amount of glycogen in normal and dysplastic epithelium as assessed semiquantitatively, was statistically significant. There was no statistically significant difference in glycogen content with different degrees of dysplasia. The diastase controlled PAS-staining may therefore be a useful method of distinguishing dysplastic from nondysplastic epithelium in doubtful cases. Pseudoepitheliomatous hyperplastic epithelium covering granular cell myoblastoma did not contain any glycogen. Five of six squamous cell carcinomas and four verrucous carcinomas contained no demonstrable glycogen. Glycogen was present in the epithelium of the cases of lichen planus and "denture hyperplasia" investigated.


[Pediatric suspensions of amoxicillin and clavulanic acid in the treatment of bacterial infections of otorhinolaryngologic importance and the upper respiratory tract].
Thirty children, 20 males and 10 females, aged 6.57 +/- 0.78 on the average (range: from 13 to 6 months), weighing 21.60 +/- 2.25 kg with bacterial infections of the upper respiratory tract and ear were admitted to the present trial. A chemotherapeutic agent based on amoxycillin and clavulanic acid in the suspension for children of 312.5 mg/5 ml (4:1 ratio) at the dosage of about 17 mg/kg in two daily administrations according to the weight of the patients was used. The therapy was prolonged for 8.87 +/- 0.30 days on the average, from a minimum of 3 to a maximum of 11 days. In the course of the treatment the symptom parameters and the objective signs progressively reduced until disappearance; the body temperature came promptly back to normal values, confirming the definite improvement and the regression of the infectious pictures. The microbiological data also fully confirmed the successful activity of the chemoantibiotic drug used. No side effects were found and, as regards local and general tolerance, no signs of an even slight impairment related to the administration of the drug were found. The final judgement expressed on the efficacy, on the basis of the more or less quick and complete symptom regression, evolution of the infectious picture and good tolerance were the following: excellent in 22 cases, good in 6, fair in 1 and not able to be evaluated in 1 case (a female patient who left off the trial).


The urban-rural disparity in nursing home quality indicators: the case of facility-acquired contractures.
To identify and quantify the sources of the urban-rural disparity in facility-acquired contracture rates in nursing homes. Survey inspection data of U.S. nursing homes from 1999 to 2008 and standardized national rural definition file from the Rural-Urban Commuting Area Codes. We estimated regressions of facility-level contracture rate as a function of urban-rural categories (urban, micropolitan, small rural town, and isolated small rural town) and other related facility characteristics to identify size of the urban-rural disparity. We used Blinder-Oaxaca decomposition techniques to determine the extent to which the disparity is attributable to the differences in facility and aggregate resident characteristics. Rural nursing homes have higher contracture rates than urban nursing homes. About half of the urban-rural disparity is explained by differences in observable characteristics among urban and rural nursing homes. Differences in staffing levels explain less than 5 percent of the disparity, case-mix explains 6-8 percent, and structure and operational characteristics account for 10-22 percent of the disparity. While a lower level and quality of staffing are a concern for rural nursing homes, facility structure and funding sources explain a larger proportion of the urban-rural disparity in the quality of care.


Dietary Exposure to Bifenthrin and Fipronil Impacts Swimming Performance in Juvenile Chinook Salmon (Oncorhynchus tshawytscha).
Two commonly used insecticides, bifenthrin and fipronil, can accumulate in the prey of juvenile Chinook salmon, yet the effects of dietary exposure are not understood. Therefore, to better characterize the effect of a dietary exposure route, juvenile Chinook salmon were fed chironomids dosed with a concentration of 9 or 900 ng/g of bifenthrin, fipronil, or their mixture for 25 days at concentrations previously measured in field-collected samples. Chinook were assessed for maximum swimming performance (Umax) using a short-duration constant acceleration test and biochemical responses related to energetic processes (glucose levels) and liver health (aspartate aminotransferase (AST) activity). Chinook exposed to bifenthrin and bifenthrin and fipronil mixtures had a significantly reduced swimming performance, although not when exposed to fipronil alone. The AST activity was significantly increased in bifenthrin and mixture treatments and glucose levels were increased in Chinook following a mixture treatment, although not when exposed to fipronil alone. These findings suggest that there are different metabolic processes between bifenthrin and fipronil following dietary uptake that may influence toxicity. The significant reductions in swimming performance and increased levels of biochemical processes involved in energetics and fish heath could have implications for foraging activity and predator avoidance in wild fish at sensitive life stages.


MG53 inhibits angiogenesis through regulating focal adhesion kinase signalling.
Mitsugumin 53 (MG53), which is expressed predominantly in striated muscle, has been demonstrated to be a myokine/cardiokine secreted from striated muscle under specific conditions. The important roles of MG53 in non-striated muscle tissues have also been examined in multiple disease models. However, no previous study has implicated MG53 in the control of endothelial cell function. In order to explore the effects of MG53 on endothelial cells, human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant human MG53 (rhMG53). Then, rhMG53 uptake, focal adhesion kinase (FAK)/Src/Akt/ERK1/2 signalling pathway activation, cell migration and tube formation were determined in vitro. The efficacy of rhMG53 in regulating angiogenesis was also detected in postnatal mouse retinas. The results demonstrated that rhMG53 directly entered into endothelial cells in a cholesterol-dependent manner. The uptake of rhMG53 directly bound to FAK in endothelial cells, which resulted in a significant decrease in FAK phosphorylation at Y397. Accompanied by the dephosphorylation of FAK, rhMG53 uncoupled FAK-Src interaction and reduced the phosphorylation of Src at Y416. Consequently, the activation of FAK/Src downstream signalling pathways, such as Akt and ERK1/2, was also significantly inhibited by rhMG53. Furthermore, rhMG53 remarkably decreased HUVEC migration and tube formation in vitro and postnatal mouse retinal angiogenesis in vivo. Taken together, these data indicate that rhMG53 inhibits angiogenesis through regulating FAK/Src/Akt/ERK1/2 signalling pathways. This may provide a novel molecular mechanism for the impaired angiogenesis in ischaemic diseases.


The proliferative potential of human cardiac stem cells was unaffected after a long-term cryopreservation of tissue blocks.
Human c-kit-positive cardiac stem cells (CSCs) have been used to treat patients suffering from ischemic cardiomyopathy. This study aimed to investigate whether a long-term storage of cardiac tissues would influence the growth potential of the subsequently isolated CSCs. A total of 34 fresh samples were obtained from various cardiac regions [right atrium (RA), left atrium (LA), and/or left ventricle (LV)] of 21 patients. From 12 of these patients, 18 samples kept frozen for ~2 years were employed to prepare and characterize the CSCs. After confirming the specificity of the cell sorting by c-kit immunolabeling, the growth rate (number of doublings per day), BrdU positivity, and colony forming unit (CFU) were measured in each CSC population; the values were compared among distinct cardiac regions as well as between fresh and frozen tissues from which CSCs were derived. Among independent measurements indicating growth potential, the growth rate and BrdU positivity remarkably correlated in freshly prepared CSCs. The cells obtained from every examined region displayed a high proliferative capacity with the growth rate of 0.48±0.19 and the BrdU positivity of 15.0%±7.6%. The right atrial CSCs tended to show a greater growth than those in the other two areas. Similarly, the CSCs were isolated from tissue blocks, cryopreserved for ~2 years, and compared with CSCs derived from the fresh specimens of the same patients. Importantly, we were able to obtain and culture CSCs from every frozen material, and their proliferative potential, represented by the growth rate of 0.47±0.22 and the BrdU positivity of 13.7%±7.9%, was not inferior to that of the freshly prepared cells. The long-term cryopreservation of cardiac tissues did not affect the growth potential of the derivative CSCs. Our findings should expand the therapeutic applications of these cells over a longer time span.


Effect of microgravity changes on virus infection in mice.
We have analyzed the effect of stress caused by the exposure of BALB/c mice to microgravity change on the susceptibility to herpes simplex virus type 1 (HSV-1) infection. Mice exposed to microgravity for 10 seconds showed a decreased rate of survival from HSV-1 infection. Murine interferon (MuIFN) administration to mice after exposure to microgravity partly diminished the decrease in survival. After repeated exposure to microgravity, mice showed tolerance to the stress. These results indicate that microgravity-stress leads to a down regulation of resistance to virus infection in relation to the modulation of the central nerve system in mice. Responsibility of the immune system dependent on cytokines, including IFN, for down regulation of the resistance is also suggested. Tail-suspended mice were also less resistant to virus infection.


Metastasis therapies for renal cancer.
Although novel targeted therapies for metastatic renal cell carcinoma (RCC) are emerging, metastasectomy still remains the only potentially curable intervention and plays an important role both in disease control, cancer-specific survival (CSS) and overall survival (OS). A systematic review was conducted in 2014 by the European Association of Urology RCC guidelines panel to summarize evidence on the subject at hand. The purpose of this review is to update the current evidence base. A total of 17-19% of initially nonmetastatic patients with later RCC metastasis are potentially curable. Complete metastasectomy still remains the sole curative option, continues to show improved OS and CSS and is suggested to defer time to palliative targeted therapy. Resectability, long time to recurrence, good performance status and oligometastatic disease have better benefit of metastasectomy. Stereotactic radiotherapy remains an excellent option for local tumor control and symptom control in patients with RCC brain and bone metastases. Minimal-invasive options such as thermal ablation are evolving, albeit the evidence base is small. Novel trials are investigating sequencing of metastasectomy and targeted therapy with results pending. Metastasectomy continues to be supported as beneficial for OS, CSS and progression-free survival in patients with good prognostic factors.


Purification and characterization of the flagellar hook-basal body complex of Bacillus subtilis.
The flagellar hook-basal body (HBB) complex of the Gram-positive bacterium Bacillus subtilis was purified and analysed by electron microscopy, gel electrophoresis, and amino acid sequencing of the major component proteins. The purified HBB complex consisted of the inner (M and S) rings, a rod and a hook. There were no outer (P and L) rings that are found in Gram-negative bacteria. The hook was 15 nm in thickness and 70 nm in length, which is thinner and longer than the hook of Salmonella typhimurium. The hook protein had an apparent molecular mass of 29 kDa, and its N-terminal sequence was identical to that of B. subtilis FIgG, which was previously reported as a rod protein. The sequence of the reported FIgG protein of B. subtilis is more closely related to that of FIgE (the hook protein) rather than FIgG (the rod protein) of S. typhimurium, in spite of the difference of the apparent molecular masses between the two hook proteins (29 kDa versus 42 kDa). The hook-basal body contained six major proteins (with apparent molecular masses of 82, 59, 35, 32, 29 and 20 kDa) and two minor proteins (23 kDa and 13 kDa), which consistently appeared from preparation to preparation. The N-terminus of each of these proteins was sequenced. Comparison with protein databases revealed the following polypeptide-gene correspondences: 82 kDa, fIiF; 59 kDa, fIgK; 35 kDa, orfF; 32 kDa, yqhF; 23 kDa, orf3 of the fIaA locus; 20 kDa, fIgB and fIgC; 13 kDa, not determined. The band at 20 kDa was a mixture of FIgB and FIgC, as revealed by two-dimensional gel analysis. Characteristic features of B. subtilis HBB are discussed in comparison with those of S. typhimiurium.


[Thrombolysis in acute transmural heart infarction: length of ischemia as a determinant of late results after 15 months].
In 28 patients the effect of coronary artery reperfusion in acute transmural myocardial infarction was evaluated by the clinical and hemodynamic results obtained after 15 months. Patients with successful reperfusion within 4 hours after onset of symptoms were assembled in group A1 (n = 11), patients with successful reperfusion after more than 4 hours in group A2 (n = 7). Group B consists of 10 patients with unsuccessful reperfusion. Left ventricular ejection fraction (radionuclide ventriculography) and the perfusion defect (thallium-201 scintigraphy) were measured acutely and after 15 months (at rest and during exercise). The coronary anatomy and the regional ejection fraction of infarct area were determined acutely and after 4 weeks by cineangiography. Serum creatine kinase activity was measured serially during the acute phase of the infarction. Before the acute intervention, the patients of the 3 groups were comparable with regard to killip class, location of infarction, number of previous infarctions, coronary anatomy, left ventricular ejection fraction, thallium-201 perfusion defect and base-line serum creatine kinase activity. During acute infarction peak creatine kinase activity tended to be lower in group A1 (1296 U/l) than in group A2 (2100 U/l, NS) and in group B (2240 U/l, NS). After 4 weeks regional ejection fraction of infarct area was higher in group A1 (36%) than in groups A2 (24%, NS) and B (20%, p less than 0.05). After 15 months the thallium-201 perfusion defect was smaller in group A1 (7%) than in groups A2 (28%, p less than 0.05) and B (34%, p less than 0.01). At the same time left ventricular ejection fraction was higher in group A1 (52%) than in groups A2 (34%, p less than 0.05) and B (35%, p less than 0.05). Fifteen months after acute infarction patients in group A1 tended to reach a higher workload during exercise (118 watts) compared with patients of groups A2 (82 watts, NS) and B (86 watts, NS).(ABSTRACT TRUNCATED AT 250 WORDS)


Left Ventricular Architecture, Long-Term Reverse Remodeling, and Clinical Outcome in Mild Heart Failure With Cardiac Resynchronization: Results From the REVERSE Trial.
This study sought to determine the effects of abnormal left ventricular (LV) architecture on cardiac remodeling and clinical outcomes in mild heart failure (HF). Cardiac resynchronization therapy (CRT) is an established treatment for HF that improves survival in part by favorably remodeling LV architecture. LV shape is a dynamic component of LV architecture on which contractile function depends. Transthoracic 2-dimensional echocardiography was used to quantify changes in LV architecture over 5 years of follow-up of patients with mild HF from the REVERSE study. REVERSE was a prospective study of patients with large hearts (LV end-diastolic dimension ≥55 mm), LV ejection fraction <40%, and QRS duration >120 ms randomly assigned to CRT-ON (n = 419) and CRT-OFF (n = 191). CRT-OFF patients were excluded from this analysis. LV dimensions, volumes, mass index, and LV ejection fraction were calculated. LV architecture was assessed using the sphericity index, as follows: (LV end-diastolic volume)/(4/3 × π × r3) × 100%. LV architecture improved over time and demonstrated significant associations between LV shape, age, sex, and echocardiography metrics. Changes in LV architecture were strongly correlated with changes in LV end-systolic volume index and LV end-diastolic volume index (both p < 0.0001). Sphericity index emerged as a predictor of death and HF hospitalization in spite of the low adverse event rate. A decrease in LV end-systolic volume index >15% occurred in more than two-thirds of patients, which indicates considerable reverse remodeling. We demonstrated that change in LV architecture in patients with mild HF with CRT is associated with structural and functional remodeling. Mean LV filling pressure was elevated, and the inability to lower it was an additional predictor of HF hospitalization or death. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154).


Chemotherapy of ovarian cancer directed by the human tumor stem cell assay.
The human tumor stem cell assay (HTSCA) has been used to study the in vitro sensitivity rates of anticancer drugs used in the treatment of 115 patients with previously untreated and relapsing ovarian cancer. The data from these studies have identified patterns of cross resistance and residual sensitivity between these agents, and have allowed the prospective selection of single agents possessing in vitro activity for the treatment of 32 patients with relapsing disease. cis-Platinum and vinblastine were the most active agents in vitro against ovarian TCFUs from both previously untreated and relapsing patients. Prior therapy with even one drug was associated with the acquisition of resistance to several classes of compounds (e.g., melphalan resistance was almost always associated with in vitro adriamycin resistance, P less than 0.001). A clinical trial yielding similar data would have required nearly 450 evaluable ovarian cancer patients. In 11 of 32 patients in vitro testing predicted sensitivity to single agents: eight of these had partial remissions for a predictive accuracy of 73%. In 33 instances the HTSCA had 100% accuracy in predicting the lack of clinical response. Thus, the HTSCA for advanced ovarian cancer appears to have a similar predictive accuracy rate to the estrogen receptor assay for predicting the response to hormonal therapy for disseminated breast cancer.


Coenzyme A-independent transacylation in amnion-derived (WISH) cells.
Total membranes or microsomal fractions prepared from the amnion-derived WISH cell line posses a coenzyme A-independent transacylase activity. The transacylase utilizes 1-alkenyl- and 1-alkyl-2-lysoglycerophospholipids as preferred acceptors. Marginal transacylation was observed with 1-acyl-2-lysoglycerophospholipids. The reaction occurred in the presence of ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid and was not affected by phospholipase A2 inhibitors. Both 1-acyl- or 1-alkyl-glycerophosphocholines containing an arachidonoyl residue in the sn-2 position were effective as donors, while 2-oleoyl- or 2-palmitoyl-glycerophosphocholines were ineffective. The presence of the transacylase, the specificity of the substrates, and the stability of the 1-alkenyl bond provide a biochemical model that may explain the increased proportion of a highly enriched arachidonate-containing phosphatidyl-ethanolamine-plasmalogens fraction that is found in amnion at term.


Testing for intron function in the essential Saccharomyces cerevisiae tRNA(SerUCG) gene.
The gene sup61+, which codes for the essential Saccharomyces cerevisiae tRNA(SerUCG), is the only single-copy tRNA gene in this organism know to contain an intron. To assess the role of this intron in tRNA gene expression, an intron-deleted sup61+ gene was constructed in vitro and introduced into the yeast genome. Isogenic intron- and intron+ strains were found to be indistinguishable by criteria that include growth rates, ability to undergo meiosis, levels of mature tRNA(SerUCG) transcribed in vivo, and the suppressor efficiency of amber- and ochre-specific alleles of this gene.


Effect of positive charge in VIP 16gamma-glutamyl diamino derivatives on hVPAC1 and hVPAC2 receptor function.
Increase of VPAC receptor s binding to the (16)gamma-glutamyl diaminopropane vasoactive intestinal peptide (VIP-DAP) agonist, a vasoactive intestinal polypeptide (VIP) structural analogue containing a positive charge at position 16, has confirmed the importance of a positive charge at this site. By investigating the effect of distance from the peptide backbone Calpha of a positive charge in position 16, data are reported here concerning: (i) a novel chemical method used for the synthesis of a new family of (16)gamma-glutamyl diamine VIP derivatives differing among them for single carbon atoms and including diaminoethane (VIP-DAE2), diaminopropane (VIP-DAP3), diaminobutane (VIP-DAB4), diaminopentane (VIP-DAP5), and diaminohexane (VIP-DAH6); (ii) functional characterization of these compounds on human VPAC1 and VPAC2 receptors. In more detail, the EC50 and IC50 values, when measured as a function of the alkylic chain length, show in more detail, that the use of VIP-DAB4 derivative changes the IC50 but not the EC50, thus indicating on hVPAC2 receptor an unexpected relationship between binding and activity that differs from that obtained on hVPAC1.


Knowing the gap: medication use, adherence and blood pressure control among patients with hypertension in Indonesian primary care settings.
Hypertension is a major risk factor for global disease burden, however, little is known regarding the profiles of patients with hypertension in Indonesian primary care settings. This study aimed to profile medication use, adherence to medications and lifestyle modifications as well as blood pressure control among patients with hypertension in Indonesian primary health centres (PHCs). A cross-sectional study design used a structured data collection tool (questionnaire and checklist). Patients aged ≥18 years with a diagnosis of hypertension, and prescribed an antihypertensive medication, and attending follow-up visits in the five PHCs in Surabaya, Indonesia, during a two-week study period (May-October 2019) were included. Descriptive analyses summarised the data, while binary logistic regression provided any independent associations between adherence profiles and blood pressure control. Of 457 eligible patients, 276 patients consented: PHC A (n = 50/91), PHC B (n = 65/116), PHC C (n = 47/61), PHC D (n = 60/88), PHC E (n = 54/101), giving an overall response rate of 60.4%. Patients were mainly treated with a single antihypertensive medication, i.e., amlodipine (89.1%), and many had not achieved blood pressure targets (68.1%). A majority reported notable levels of non-adherence to medication (low/intermediate, 65.2%) and poor healthy lifestyle behaviours, particularly physical activity (inadequate, 87.7%) and discretionary salt use (regularly, 50.4%). Significant associations were found between low medication adherence, discretionary salt use and smoking, with blood pressure control. The study findings provide the evidence needed to improve the current level of sub-optimal blood pressure management among patients with hypertension in these Indonesian primary care settings. Particular emphasis should be placed on antihypertensive medication adherence and healthy lifestyle behaviours through locally tailored hypertension-related interventions.


Discriminating neoantigenic differences between fibrinogen and fibrin derivatives.
Discrimination between the physiological cleavage fragments of fibrinogen and fibrin offers an approach to differentiation between fibrinogenolytic processes and fibrinolysis after coagulation. By use of the cleavage-associated neoantigen of fibrinogen (fg-D(neo)) as a molecular marker, characteristic differences between the D regions of fibrinogen derivatives and fibrin derivatives can be demonstrated. The expression of fg-D(neo) by X, Y, D:E complex, and D-fragments of fibrinogen or fibrin is shown to be quantitative and unitary. Characteristic differences between fg-D(neo) sites present on fibrinogen cleavage fragments, as contrasted to fibrin cleavage fragments, are indicated by different competitive inhibition slopes, and appear to reflect differential binding affinity of selected anti-fg-D(neo) antibodies for the specific molecular site. There is a linear relationship between the slope of quantitative competitive inhibition and the relative molar ratio of fibrinogen and fibrin derivatives. Identical immunochemical expressions are observed in vitro and in vivo, and support the thesis that cleavage in vivo is produced by plasmin. The differential immunochemical features of fg-D(neo) expression may be the result of stable conformational and/or subtle structural differences between the D region of fibrinogen and fibrin cleavage fragments and suggest that precise changes in the D region are associated with the fibrin transition. These molecular features not only provide additional insight into the molecular immunology and structure of fibrinogen, but also appear to offer a new molecular approach to discrimination between fibrinogenolytic mechanisms as contrasted to fibrinolysis secondary to coagulation.


Advances in 3D printing techniques for cartilage regeneration of temporomandibular joint disc and mandibular condyle.
Temporomandibular joint (TMJ) osteoarthritis causes fibrocartilage damage to the TMJ disc and mandibular condyle, resulting in local pain and functional impairment that further reduces patients' quality of life. Tissue engineering offers a potential treatment for fibrocartilage regeneration of the TMJ disc and mandibular condyle. However, the heterogeneous structure of TMJ fibrocartilage tissue poses significant challenges for the fabrication of biomimetic scaffolds. Over the past two decades, some researchers have attempted to adopt three-dimensional (3D) printing techniques to fabricate biomimetic scaffolds for TMJ fibrocartilage regeneration, but publications on such attempts are limited and rarely report satisfactory results, indicating an urgent need for further development. This review outlines several popular 3D printing techniques and the significant elements of tissue-engineered scaffolds: seed cells, scaffold materials, and bioactive factors. Current research progress on 3D-printed scaffolds for fibrocartilage regeneration of the TMJ disc and mandibular condyle is reviewed. The current challenges in TMJ tissue engineering are mentioned along with some emerging tissue-engineering strategies, such as machine learning, stimuli-responsive delivery systems, and extracellular vesicles, which are considered as potential approaches to improve the performance of 3D-printed scaffolds for TMJ fibrocartilage regeneration. This review is expected to inspire the further development of 3D printing techniques for TMJ fibrocartilage regeneration.


A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene.
Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4-ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization.


Trajectory and mortality of preserved ratio impaired spirometry: the Rotterdam Study.
Preserved ratio impaired spirometry (PRISm) is a heterogeneous condition but its course and disease progression remain to be elucidated. We aimed to examine its prevalence, trajectories and prognosis in the general population.In the Rotterdam Study (population-based prospective cohort) we examined prevalence, trajectories and prognosis of subjects with normal spirometry (controls; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥0.7, FEV1 ≥80%), PRISm (FEV1/FVC ≥0.7, FEV1 <80%) and chronic obstructive pulmonary disease (COPD) (FEV1/FVC <0.7) at two study visits. Hazard ratios with 95% confidence intervals for mortality (until December 30, 2018) were adjusted for age, sex, body mass index, current smoking and pack-years.Of 5487 subjects (age 69.1±8.9 years; 7.1% PRISm), 1603 were re-examined after 4.5 years. Of the re-examined PRISm subjects, 15.7% transitioned to normal spirometry and 49.4% to COPD. Median lung function decline was highest in subjects with incident PRISm (FEV1 -92.8 mL·year-1, interquartile range (IQR) -131.9- -65.8 mL·year-1; FVC -93.3 mL·year-1, IQR -159.8- -49.1 mL·year-1), but similar in persistent PRISm (FEV1 -30.2 mL·year-1, IQR -67.9- -7.5 mL·year-1; FVC -20.1 mL·year-1, IQR -47.7-21.7 mL·year-1) and persistent controls (FEV1 -39.6 mL·year-1, IQR -64.3--12.7 mL·year-1; FVC -20.0 mL·year-1, IQR -55.4-18.8 mL·year-1). Of 5459 subjects with informed consent for follow-up, 692 (12.7%) died during 9.3 years (maximum) follow-up: 10.3% of controls, 18.7% of PRISm subjects and 20.8% of COPD subjects. Relative to controls, subjects with PRISm and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2-4 had increased all-cause mortality (PRISm: HR 1.6, 95% CI 1.2-2.0; COPD GOLD 2-4: HR 1.7, 95% CI 1.4-2.1) and cardiovascular mortality (PRISm: HR 2.8, 95% CI 1.5-5.1; COPD 2-4: HR 2.1, 95% CI 1.2-3.6). Mortality within <1 year was highest in PRISm, with patients often having cardiovascular comorbidities (heart failure or coronary heart disease; 70.0%).PRISm is associated with increased mortality and this population encompasses at least three distinct subsets: one that develops COPD during follow-up, a second with high cardiovascular burden and early mortality, and a third with persistent PRISm and normal age-related lung function decline.


Obsessive-compulsive symptoms in patients with temporal lobe epilepsy.
The goals of this work were to: (1) determine the prevalence of clinically significant obsessive-compulsive (OC) symptoms in patients with temporal lobe epilepsy (TLE), (2) characterize the differences in self-reported OC symptoms in patients with TLE and a normative control group, and (3) compare the severity of OC symptoms in right and left hemisphere TLE patients. Patients with TLE (n=30) were administered the Obsessive-Compulsive Inventory (OCI). As a group, patients with TLE had a higher prevalence of OC symptoms than the nonpatient normative sample. In addition, TLE patients exhibited elevated scores on all but 3 of the 16 OCI scales and subscales. There were no reliable differences in OC symptoms in patients with right versus left hemisphere seizure foci, although the right hemisphere patients tended to score higher on both scales of the OCI.


Sensory thresholds among construction trade painters: a cross-sectional study using new methods for measuring temperature and vibration sensitivity.
Instruments that measure quantitatively sensory threshold to vibration and temperature difference were used to test 93 construction trade painters and a reference group of 105 healthy construction and industrial workers who were not painters. A "forced-choice" testing procedure, and an algorithm for threshold estimation (the "Best PEST"), was used for the Temperature Sensitivity Tester and the Vibratron. The method of limits procedure was used for the Biothesiometer. When measured with the Vibratron, painters in the older age stratum were found to have significantly higher vibration thresholds than the reference group. Painters had significantly more temperature sensitivity thresholds classified as "high" than the reference group. Among painters, exposure intensity and cumulative exposure over the past year was positively associated with vibration thresholds estimated using the Vibratron. Lifetime cumulative exposure, cumulative exposure over the previous month, and exposure intensity were positively associated with vibration thresholds estimated using the Biothesiometer.


Surgical site infection after multiple groin incisions in peripheral vascular surgery.
Patients with peripheral arterial disease (PAD) are at risk for revision surgery in the groin and therefore at potential risk for surgical site infections (SSIs). In an observational study, a cohort of patients with peripheral arterial disease was followed to examine the effect of different incision intervals on SSI-free survival. Patients, needing peripheral vascular surgery because of PAD, were retrieved from a prospectively collected database on SSIs after vascular surgery between March 2009 and January 2012, the group consisting of 720 patients. Of these, 255 patients were selected (age 71.9±10.4 y). Cox proportional hazards models were used for event-history analyses. The effect of incision interval was estimated with adjustment for a number of potential confounders. Effects were quantified by means of hazard ratios (HRs) with 95% confidence intervals (CIs). No significant effect on the incision interval on SSI-free survival was observed. After separating incisional SSIs into superficial- and deep-seated, a significant linear trend effect of the groin incision interval on deep-incisional SSI development was observed: the shorter the interval, the higher the event rate (HR 1.5 per category, 95% CI 1.1-2.1, p=0.22). Besides the incision interval, the Rutherford classification was a significant risk factor for SSI development (HR 3.0; 95% CI 2.1-4.2; p<0.0005). Revision surgery in the groin puts patients at risk for deep-incisional SSI. No effect on superficial incisional SSI development was observed. Besides the incision interval, the Rutherford classification was a significant risk factor for both superficial- and deep-incisional SSI. Quality improvement and better risk stratification schemes are suggested.


Induced mood and estimates of past success.
Depressed subjects make lower retrospective estimates of success on experimental tasks than non-depressed controls. This could be an effect of depressed mood on retrieval of information rather than a more enduring aspect of depressives' cognitive organization. To examine this possibility, elated or depressed mood was induced in normal subjects after they had performed an experimental task. Retrospective estimates of success on the task were lower when made in depressed mood than in elated mood. Control conditions suggested that the results were not effects of experimental demand.


Acetylcholinesterase in honey bees (Apis mellifera) exposed to neonicotinoids, atrazine and glyphosate: laboratory and field experiments.
In Québec, as observed globally, abnormally high honey bee mortality rates have been reported recently. Several potential contributing factors have been identified, and exposure to pesticides is of increasing concern. In maize fields, foraging bees are exposed to residual concentrations of insecticides such as neonicotinoids used for seed coating. Highly toxic to bees, neonicotinoids are also reported to increase AChE activity in other invertebrates exposed to sub-lethal doses. The purpose of this study was therefore to test if the honey bee's AChE activity could be altered by neonicotinoid compounds and to explore possible effects of other common products used in maize fields: atrazine and glyphosate. One week prior to pollen shedding, beehives were placed near three different field types: certified organically grown maize, conventionally grown maize or non-cultivated. At the same time, caged bees were exposed to increasing sub-lethal doses of neonicotinoid insecticides (imidacloprid and clothianidin) and herbicides (atrazine and glyphosate) under controlled conditions. While increased AChE activity was found in all fields after 2 weeks of exposure, bees close to conventional maize crops showed values higher than those in both organic maize fields and non-cultivated areas. In caged bees, AChE activity increased in response to neonicotinoids, and a slight decrease was observed by glyphosate. These results are discussed with regard to AChE activity as a potential biomarker of exposure for neonicotinoids.


Assessment and validation of US EPA's OncoLogic® expert system and analysis of its modulating factors for structural alerts.
OncoLogic® is a software program able to screen chemical compounds for toxicological effects. The software predicts the potential carcinogenicity of chemicals by applying rules of structure activity relationship (SAR) analysis. To validate the predictivity of OncoLogic® (Version 7.0), 123 compounds tested with the long-term carcinogenicity bioassay on rodents were extracted from the ISSCAN database and were analyzed. The concordance between the OncoLogic® SAR analysis and the bioassay results was high. To better understand the strength of the SAR science in OncoLogic®, we investigated the influence of a select group of modulating factors on the predictions by the structural alerts.


Choices in surgical treatment of rigid neurogenic and arthrogrypotic clubfeet.
Clinical experience in treating clubfoot suggests that the equinovarus deformity in the arthrogrypotic child is often comparable to the equinovarus deformity in certain neurologically impaired children. Both types of feet tend to be rigid, to resist correction, and to present problems of management different from those of idiopathic equinovarus feet. I describe a series of 18 rigid neurogenic or arthrogrypotic clubfeet in 10 children illustrating problems of diagnosis and management and pointing up the desirability of access to a broad range of surgical procedures to solve these unique problems.